Gabapentin

Gabapentin is a structural analog of gamma-aminobutyric acid (GABA) used as an antiepileptic and for neuropathic pain. FDA-approved products include Neurontin (gabapentin) capsules, tablets and oral solution, Gralise (once-daily gastroretentive tablets) and Horizant (gabapentin enacarbil extended-release tablets, a prodrug). No FDA-approved topical gabapentin product exists; compounded topical preparations are used for localized application.

• Neurontin: management of postherpetic neuralgia in adults, and adjunctive therapy for partial-onset seizures, with and without secondary generalization, in adults and children 3 years and older.
• Gralise: postherpetic neuralgia. Horizant: moderate-to-severe primary restless legs syndrome and postherpetic neuralgia in adults.
• Prescribers use compounded topical gabapentin for localized neuropathic pain and related conditions. No FDA-labeled indication or dose exists for topical use.

Gabapentin binds with high affinity to the alpha-2-delta subunit of voltage-gated calcium channels in the central and peripheral nervous system. This binding reduces calcium-dependent release of excitatory neurotransmitters. Although it is structurally related to GABA, gabapentin does not bind GABA receptors or affect GABA uptake or metabolism. The mechanism of any local action after topical application has not been established.

Oral absorption occurs by a saturable L-amino acid transporter, so bioavailability falls as the dose rises, from about 60% at 900 mg/day to about 27% at 4800 mg/day. Gabapentin is less than 3% protein bound, is not appreciably metabolized, and does not induce or inhibit hepatic enzymes.

It is eliminated unchanged in the urine with a half-life of 5 to 7 hours in normal renal function; clearance falls in proportion to creatinine clearance, and dose reduction is required in renal impairment. Hemodialysis removes gabapentin. Percutaneous absorption from compounded topical preparations is limited and variable and has not been well characterized.

• Known hypersensitivity to gabapentin or any ingredient of the product.

• Drug reaction with eosinophilia and systemic symptoms (DRESS) or multiorgan hypersensitivity, which can be fatal; discontinue if no alternative cause is found. Anaphylaxis and angioedema can occur after the first dose or later.
• Respiratory depression: serious, life-threatening breathing problems can occur with concomitant opioids or other CNS depressants, and in patients with underlying respiratory impairment or older age. Start at the lowest dose and monitor.
• Somnolence, dizziness and impaired driving ability. Suicidal behavior and ideation, as with other antiepileptic drugs; monitor for emergence or worsening of depression and unusual changes in mood or behavior.
• Withdrawal-precipitated seizures with abrupt discontinuation in epilepsy; taper gradually. Neuropsychiatric adverse events in children 3 to 12 years. Misuse and abuse have been reported, particularly in people with opioid use disorder; gabapentin is not federally controlled, but some states schedule it or require prescription-monitoring reporting.

• Opioids and other CNS depressants (benzodiazepines, alcohol, sedating antihistamines): additive CNS and respiratory depression. Morphine increases gabapentin exposure; gabapentin decreases hydrocodone exposure.
• Aluminum- and magnesium-containing antacids reduce oral gabapentin bioavailability by about 20%; give gabapentin at least 2 hours after the antacid.
• Gabapentin has no clinically meaningful pharmacokinetic interactions with other antiepileptic drugs or oral contraceptives. It can cause false-positive urine protein dipstick results.

With oral use, the most common adverse effects are dizziness, somnolence, peripheral edema, ataxia, fatigue, nystagmus, diplopia, blurred vision, tremor, weight gain, dry mouth and gastrointestinal upset. Children may have hostility, emotional lability and hyperkinesia. With topical use, local redness, stinging or irritation are the expected effects; systemic effects are possible if absorption occurs.

Based on animal data, gabapentin may cause fetal harm. Human data are limited; a North American Antiepileptic Drug Pregnancy Registry collects outcome data. Use in pregnancy only if the potential benefit justifies the risk.

Gabapentin is secreted into human milk. Breastfed infants should be monitored for sedation, and the decision to use it while breastfeeding should weigh the mother's need against the infant's exposure.

Monitor pain or seizure response, renal function for dose adjustment, sedation and respiratory status (especially with opioids or in older adults), mood and behavior for suicidality, rash or signs of hypersensitivity, and signs of misuse. With topical use, also monitor the application site.

• Neurontin (gabapentin) Prescribing Information, Viatris.
• Gralise (gabapentin) once-daily tablets Prescribing Information.
• Horizant (gabapentin enacarbil) extended-release tablets Prescribing Information.
• FDA Drug Safety Communication: serious breathing difficulties with gabapentinoids, December 2019.